KR20070007931A - Use of peptidic compounds for the prophylaxis and treatment of chronic headache - Google Patents

Abstract

The present invention is directed to the use of a class of peptide compounds for the prophylaxis and treatment of chronic headache, particularly migraines. ® KIPO & WIPO 2007

Description

Use of peptidic compounds for the prophylaxis and treatment of chronic headache}

The present invention relates to the use of peptide compounds for the prevention and treatment of chronic headaches, preferably migraine headaches.

Certain peptides are known to exhibit central nervous system (CNS) activity and are useful for the treatment of epilepsy and other CNS disorders. Such peptides disclosed in US Pat. No. 5,378,729 have the general formula (la):

Wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl R is unsubstituted or substituted with at least one electron withdrawing group or electron donating group;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each being unsubstituted, or The electron donor is substituted by a group or an electron withdrawing group;

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl Lower alkyl, or ZY, R ₂ and R ₃ are unsubstituted or substituted with at least one electron withdrawing group or at least one electron donor;

Z is O, S, S (O) _a , NR ₄ , PR ₄ , or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, Y is unsubstituted or the electron donor can be substituted with a group or electron withdrawing group When Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ or PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ or PR ₄ NR ₅ R ₇ ,

ego;

R ₄ , R ₅ , and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, and R ₄ , R ₅ , and R ₆ are unsubstituted or electron withdrawn A group or electron column may be substituted with a group;

R ₇ is R ₆ or COOR ₈ or COR ₈ ;

R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group is unsubstituted or an electron withdrawing group or electron donor can be substituted with a group;

n is 1-4;

a is 1-3.

US Pat. No. 5,773,475 also discloses other compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3-methoxy-propionamides having the formula IIa.

Where

Ar is aryl unsubstituted or substituted with halo; R ₃ is lower alkoxy; R ₁ is methyl.

U.S. Patents 5.378.729 and 5.773.475 are incorporated herein by reference. However, none of these patents disclose the use of such compounds as analgesics specific to the treatment of chronic headaches.

WO 02/074297 discloses peripheral neuropathy of the compound of formula (IIa) wherein Ar is phenyl which may be substituted with one or more halo, R ₃ is lower alkoxy containing 1-3 carbon atoms and R ₁ is methyl It relates to the use in the manufacture of pharmaceutical compositions useful for the treatment of allodynia associated with pain.

WO 02/074784 describes acute and chronic pains of different kinds and symptoms, in particular, non neuropathic inflammatory pain, for example rheumatoid arthritis pain and / or secondary inflammatory osteo-arthritis pain. The present invention relates to the use of a compound having formula (Ia) and / or formula (IIa) exhibiting anticiceptive properties for the treatment of inflammatory osteo-arthritic pain.

A person suffering from a headache may experience pain in several areas of the head, including a network of nerves extending across the scalp and certain nerves in the face, mouth, and neck. Blood vessels found along the muscles of the head and along the surface and at the base of the brain are also sensitive to pain because they contain complex nerve fibers. The bones of the cranial bones and the tissues of the brain themselves are not injured because they lack pain-sensitive nerve fibers. Called nociceptor. The distal ends of these painful nerve fibers can be stimulated by stress, muscle tension, expanded blood vessels, and other headache triggers. Vascular headaches (eg, migraines) involve abnormal work of the cerebrovascular or vascular system; Muscular contraction headaches are thought to involve tightening or straining facial and neck muscles; Traction and inflammatory headaches, on the other hand, are symptoms of other disorders, ranging from brain tumors to stroke or sinus infection. Some types of headaches have more severe disorders: sudden, severe headache; Headache associated with convulsions; Headache with confusion or unconsciousness; Headache with shock on the head; Headache associated with pain in the eyes or ears; Persistent headache in a person who had previously had a headache; Recurring headaches in children; Headache associated with fever; It is a sign of headache that interferes with normal life.

Headaches are diagnosed as vascular, muscle contraction (tension), tractional or inflammatory headaches.

The most common type of vascular headache is migraine. Migraine headaches are the most common neurological condition in developed countries. It affects about 10% of the population and is more common than diabetes, epilepsy and asthma combined. Migraine headaches are more than just headaches. This can be a debilitating condition that seriously affects the quality of life of patients and their families. Seizures can be almost incapacitated, causing patients to give up their daily activities for almost three days. Even when symptoms disappear, the patient may live in fear of the next seizure. Migraine pain is often described as severe pulsing or throbbing pain in some parts of the head. This often involves sensitivity to light and sound, nausea and vomiting. Migraine headaches are three times more common in women than men. Some patients can foresee the onset of migraine headaches because they are preceded by a visually impaired "aura" such as flashing lights, jagged lines or temporary loss of vision. People with migraine tend to have recurrent attacks caused by food or sleep deprivation, exposure to light, or hormonal irregularities (only in women). Anger, stress, or relaxation after stress can also be a trigger. For many years, scientists believed that migraine headaches were associated with the expansion and contraction of blood vessels in the head. The researchers now believe that migraines are caused by genetic abnormalities in genes that control the activity of certain cell populations in the brain. There are two ways to approach the treatment of migraine with drugs: prevention of seizures or relief of symptoms during a seizure. Many people with migraines take drugs originally developed for epilepsy and depression to prevent future seizures, and when they happen, they are called triptans, which relieve pain and restore function. Both approaches are used to treat seizures with medication.

In addition to migraine headaches, the most common type of vascular headache is a toxic headache caused by heat. Pneumonia, measles, mumps, and tonsillitis are among the diseases that can cause severe toxic vascular headaches. Toxic headaches can also arise from the presence of extraterrestrial compounds in the body.

Other types of vascular headaches include "clusters," which cause headaches due to repeated symptom of pain and elevated blood pressure. Clustering headaches, named for recurring groups in weeks or months at approximately the same time of day or night, begin with small pain around one eye and eventually spread to the face. The pain is rapidly intensified, for example, forcing the patient to hang out on the floor or to swing in a chair. Other symptoms include stuffy nose, runny nose, and drooping eyelids over red, teary eyes. Cluster headaches last 30 to 45 minutes, but the sense of security that people feel at the end of a seizure is usually mixed with fear of waiting for relapse. Cluster headaches can strangely disappear for months to years. Many people have cluster seizures during spring and autumn. Worst of all, chronic cluster headaches can last for years. Cluster seizures can occur at any age, but usually begin between the 20s and 40s. Unlike migraine headaches, cluster headaches are more common in men and are not inherited by family members. Paradoxically, nicotine contracting arteries and alcohol expanding arteries all cause cluster headaches. The exact association between these components and cluster seizures is unknown. Sudden onset of cluster headaches and short durations can make it difficult to treat cluster headaches, but researchers have identified several effective drugs for these headaches. The antimigraine drug sumatriptan can relieve cluster headaches if taken at the first sign of a seizure. Injection of dihydroergotamine, a type of ergotamine tartrate, is sometimes used to treat cluster headaches. Corticosteroids can also be used orally or by intramuscular injection. For example, seizures can be prevented by taking anti-epileptic drugs such as valproic acid.

Muscle contraction (tension) headaches are named for the contractions of the neck, face, and skull muscles caused by stressful events as well as the role played by stress in causing the pain. Stress headaches are a serious but temporary form of muscle contractile headaches. The pain is mild or moderate and feels the pressure applied to the head or neck. The headache usually goes away after the cycle of stress is over. Ninety percent of all headaches are classified as stress / muscular contractions. In contrast, chronic muscle contractile headaches can last for weeks, months and sometimes years. Pain associated with this headache is often described as a tight band around the head or the feeling of a fixed cast on the head and neck. The pain is constant and usually felt on either side of the head. Chronic muscular contractile headaches can cause cranial pain, even combing the head can cause pain. In the past, many scientists believed that the main cause of pain in myotropic headache was sustained muscle tension. However, an increasing number of experts now believe that much more complicated mechanisms are the cause.

Originally, myotrophic headache involves nausea, vomiting, and blurred vision, but there are no pre-headache symptoms such as migraine headaches. Muscular contractions, like migraines, are not associated with hormones or food and do not have strong genetic links. Investigations have shown that for many people, chronic muscle contractile headaches are caused by depression and anger. These people have headaches in the early morning or evening when they are expected to crash in the office or at home. Emotional factors are not the only triggers for muscle contractile headaches. Any physical posture that strains the head and neck muscles, for example, holding one's chin down when reading a book, writing for a long time under dark light, or placing a phone between the shoulders and ears Chewing things, or even gum, can cause head and neck pain. Acute tension headaches not associated with the disease are treated with painkillers such as aspirin and acetaminophen. Stronger analgesics such as propoxyphene and codeine are sometimes prescribed. However, excessive use of such drugs can lead to dependencies. People with chronic muscle contractile headaches can also be helped by taking antidepressants or MAO inhibitors. Mixed muscle contractions and migraine headaches are sometimes treated with antiepileptic drugs or barbiturate compounds, which relieve nerve activity in the brain and spinal cord.

Like other types of pain, headaches can act as warning signs of more serious disorders. This is especially true for headaches caused by traction or inflammation. A traction headache can occur when the pain sensations in the head are pulled, stretched, or repositioned, such as when the eye muscles are tense to compensate for eye fatigue. Inflammation headaches include headaches associated with meningitis as well as headaches resulting from diseases of the sinuses, spine, neck, ears and teeth. Ear and tooth inflammation as well as glaucoma can cause headaches. In oral or dental disorders, headache is experienced as pain in the entire head, including the face. These headaches are cured by fixing the underlying problem. This may involve surgery, antibiotics or other drugs. Various types of features of more severe traction and inflammatory headaches include disorders such as brain tumors, strokes, spinal taps, trigeminal neuralgia, head trauma, arteritis or It changes according to meningitis.

Leao (Leao AAP (1944) spreading in 1944 depression of activity in the cerebral cortex . Cortical spreading depression (CSD), previously described by J Neurophysiol 7: 359-390), is a function of cortical activity that spreads locally through the tissue at a rate of about 3 mm / min. It is a temporary suppression. This is associated with dilatation of the pial arteriole resulting in hypoperfusion of the cerebral blood flow (CBF), which involves long perfusion for several hours. The underlying mechanisms and physiological roles of these blood flow-related changes observed in CSD are still not fully understood. Various vasoactive parenchymal metabolites, such as K ⁺ , CO ₂ , adenosine, NO and glutamate, are known to be released during CSD and are known to be involved in pial vasodilatation. Can contribute. In addition, neurotransmitters released from perivascular nerve fibers surrounding cortical pial vessels can also participate in CSD-associated vasodilation. These neurotransmitters mainly belong to the tertiary nervous system, sympathetic nervous system and parasympathetic nervous system. Calcitonin gene-related peptide, substance P and neurokinin A are immunohistochemically ipsilateral division of trigeminal ganglia cells. It was found to be a transporter of perivascular tertiary nerves originating from) and continues to the nasociliary nerve. The trigeminovascular system is the anatomical substrate in the major hypothesis of migraine pathophysiology. Three-dimensional neurotransmitters (eg CGRP) contribute substantially to vasodilation in several physiological and pathophysiological conditions. As evidenced by the introduction of c-fos, the brain stem nucleus caudalis is activated in CSD, which is blocked by meningeal deafferentation. CSD activates three-dimensional nerves and potentially releases neurotransmitters from these nervous systems.

There is strong evidence that serves as an early symptom of visual precursors and pain in migraine headaches. Bolay et al. (Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA, 2002, Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine , Nat. Med. 8: 136-42) demonstrate that CSD activates trigeminovascular afferents and causes a series of cortical meningeal and brainstem events consistent with the onset of headache. The relationship between migraine precursors and headaches was established. CSD is characterized by selective improvement of long-term blood flow in the meningeal artery and activation of neurokinin-1-receptor mechanisms in response to the activity of tertiary and parasympathetic nerves. plasma protein leakage in the mater). The results provide a neural mechanism by which extracerebral celphalic blood flow is associated with brain events; This mechanism accounts for vasodilation during headaches and links the delivery of headache pain by the tertiary nerves to intense neurometabolic brain activity.

Numerous evidence suggests the involvement of CSD in cerebrovascular disease. Damage to brain tissue during ischemia depends on a complex series of physiological responses and reduced cellular cascades involving dynamic interactions between the various cells in the region of the damaged tissue. Experimental studies support the concept that there is a severe ischemic core and focal ischemic insult and the ischemic core is surrounded by a region of reduced perfusion, i.e., ischemic penumbra. Within the ischemic core, the lack of oxygen and glucose delivery leads to a rapid decrease in energy storage and cell death. At the heart of the hypothesis of neuronal salvage is the concept of the ischemic periphery. The periphery is a region where metabolic capacity is inhibited but destruction is avoided. The etiology of ongoing cell damage and death in the peripheral zone has been identified to some extent. Evidence suggests that CSD plays a role in the process of ischema-infarction tissue damage. A significant increase in extracellular potassium occurs in the ischemic core. The high potassium concentration of the ischemic focus initiates the diffusion of potassium ions into the adjacent normally perfused cortex during the initial stages of local ischemia, and the surrounding radish at the rim of the focus. It has been suggested that the intact tissue causes the progression of CSD waves. This CSD wave creates an additional metabolic burden on the tissue so far intact and thus contributes to the growth of the ischemic core. The occurrence of CSD is observed for a period of about 2 hours after ischemia, followed by shorter intervals of increased CSD susceptibility that disappear at 3-4 hours after the onset of ischemia. Significantly longer CSD waves than those observed in the intact cortex can be potentially dangerous because they involve additional glutamate release and the influx of calcium into the neurons. In the energy deficient neurons seen in the ischemic periphery, this is sufficient to initiate a cell death cascade. Thus, preventing the expression of CSD after the ischemic cycle can reduce ischemic brain injury.

Other clinical indications associated with CSD include intracranial hemorrhage and head injury. Some biochemical changes in the composition of the microenvironment during brain injury (eg high lactate and glucose concentrations in the cerebrospinal fluid) are also observed during CSD. In addition, in a single case CSD can be observed in the cortex of the living human of a patient with severe head injury. Following intracranial bleeding, delayed ischemic deficits are observed. CSD is believed to be important in this delayed ischemic defect (Gorji A. Spreading depression: a review of the clinical relevance . Brain Res. Rev. 38,2001; 33-60). As a result, blocking CSD can prevent the long-term consequences of intracranial bleeding and head injury.

Another clinical syndrome associated with CSD is transient global amnesia. Temporary amnesia is characterized by a complete loss of memory and a sudden onset of learning ability, usually occurring at the middle age. The memory loss seizures, for example, occur during migraine precursors, while CSD is observed during the migraine precursors. In animal experiments, the introduction of cortical or subcortical CSD can cause memory loss and learning disorders. This proves that blocking CSD can be beneficial for temporary memory loss.

The use of compounds of formula (Ib) and / or formula (IIb) for the inhibition of cortical diffusivity (CSD) has not been reported. Accordingly, the present invention relates to the use of compounds of formula (Ib) and / or (IIb) for the preparation of pharmaceutical compositions for the prevention, alleviation, and / or treatment of headaches, especially chronic headaches such as migraine. The invention also includes, but is not limited to, CSD, such as cerebral ischemia during stroke or cardiovascular surgery (eg, traumatic brain injury, subarachnoid hemorrhage, or transient memory loss). And the use of a compound of formula (Ib) and / or (IIb) for the preparation of a pharmaceutical composition for the prevention, alleviation, and / or treatment of all types of pain conditions associated with and / or caused by CSD. Preferably, but not limited to, migraine headaches or other types of chronic headaches of central and peripheral origin (eg, but not limited to cluster headaches, tension headaches or overuse of drugs, cranial nerves) for the preparation of a pharmaceutical composition for the prevention, alleviation, and / or treatment of chronic headaches associated with and / or caused by CSD such as cranial neuralgia, secondary headaches associated with brain trauma and vascular or metabolic disorders). It relates to the use of compounds of formula (lb) and / or (lb).

Surprisingly, the use of compounds Ib or / and IIb, in particular (R) -2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927), has shown significant inhibition of CSD and calcitonin inheritance in animal models for migraine headaches. CSD-induced release of the related peptide (CGRP) was shown.

The invention can be applied to animals, especially mammals including humans.

Compounds according to the invention useful for the prevention, alleviation, and / or treatment of headaches and / or conditions associated with and / or caused by CSD, in particular chronic headaches such as migraine, have the formula (Ib).

Wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl R is unsubstituted or substituted with at least one electron withdrawing group, and / or at least one electron donor with a group;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, respectively Is unsubstituted or substituted with at least one electron donating group and / or at least one electron withdrawing group;

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or ZY, R ₂ and R ₃ are unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron column;

Z is O, S, S (O) _a , NR ₄ , NR ' ₆ , PR ₄ , or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, Y is unsubstituted, or at least one The electron donor may be substituted with a group and / or at least one electron withdrawing group, and when Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , or N ⁺ R ₅ R ₆ R ₇ ,

이고;

ego;

R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, wherein R' ₆ may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron column;

R ₄ , R ₅ , and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, and R ₄ , R ₅ , and R ₆ are independently unsubstituted, or At least one electron withdrawing group and / or at least one electron column may be substituted with a group;

R ₇ is R ₆ or COOR ₈ or COR ₈ and R ₇ may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donor;

R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donor;

n is 1-4;

a is 1-3.

Preferably, the compound has the general formula (IIb)

Where

Ar is aryl, in particular phenyl, unsubstituted or substituted with at least one halo; R ₃ is -CH ₂ -Q and Q is lower alkoxy; R ₁ is lower alkyl, in particular methyl.

The present invention is also useful for the prevention, alleviation, or / and treatment of headaches, in particular for the prevention, alleviation or / and treatment of headaches, and / or disorders associated with and / or caused by CSD, such as migraine headaches. And / or to a pharmaceutical composition comprising a compound according to formula (IIb).

Compounds of formula (Ia) are disclosed in US Pat. No. 5,378,729, the contents of which are incorporated by reference.

When used alone or in combination with other groups, a "lower alkyl" group is lower alkyl comprising 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, and may be straight or branched. Such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trivalent butyl, amyl, hexyl and the like.

A "lower alkoxy" group is lower alkoxy containing 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, and may be straight or branched. Such groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

"Aryl lower alkyl" groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl and the like.

The term "aryl", when used alone or in combination, refers to an aromatic group comprising 6 to 18 ring carbon atoms and up to 25 carbon atoms in total and comprising a multinuclear aromatic compound. Such aryl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and are fused rings. As used herein, multinuclear aromatic compounds are intended to include bicyclic and tricyclic fused aromatic ring systems comprising 10-18 ring carbons and up to 25 carbon atoms in total. Aryl groups include phenyl and polynuclear aromatics such as naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Aryl groups also include groups such as ferrocenyl. The aryl group may be unsubstituted or may be monosubstituted or multisubstituted with an electron withdrawing group and / or electron donor as described below.

"Lower alkenyl" is an alkenyl group containing 2 to 6 carbon atoms and at least one double bond. Such groups may be straight or branched, and may be in Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z) -2-pentenyl, (E) -2-pentenyl, (Z) -4 -Methyl-2-pentenyl, (E) -4-methyl-2-pentenyl, pentadienyl such as 1,3 or 2,4-pentadienyl and the like.

The term "lower alkynyl" is an alkynyl group containing 2 to 6 carbon atoms and may be straight as well as branched. It is ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl And groups such as 3-hexynyl and the like.

The term "lower cycloalkyl", when used alone or in combination, is a cycloalkyl group containing from 3 to 18 ring carbon atoms and up to 25 carbon atoms in total. Such cycloalkyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. Cycloalkyls can be fully saturated or partially saturated. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decarinyl, hydroindanyl, indanyl , Pliers, pinenyl, adamantyl, and the like. Cycloalkyls include cis or trans forms. The cycloalkyl group may be unsubstituted or may be monosubstituted or multisubstituted with an electron withdrawing group and / or electron donor as described below. Moreover, the substituents may be at the endo or exo position in the branched bicyclic system.

The term "electron withdrawal and electron giving" refers to the ability of a substituent to attract or give electrons. Each capability of the substituents is in contrast to the ability of hydrogen when the hydrogen atoms occupy the same position in the molecule. These terms are well understood by those of ordinary skill in the art and discussed by J. March, John Wiley and Sons in Advanced Organic Chemistry, New York, NY, pp. 16-18 (1985), The discussion therein is incorporated herein by reference. Electron withdrawing groups include halo including bromo, fluoro, chloro, iodo and the like; Nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxamido, aryl, tetravalent ammonium, and haloalkyl such as trifluoromethyl, aryl lower alkanoyl, carvalkoxy and the like. Electron donating groups include groups such as hydroxy and lower alkoxy including methoxy, ethoxy and the like; Lower alkyl such as methyl, ethyl and the like; Amino, lower alkylamino, di (lower alkyl) amino and aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) and the like. One of ordinary skill in the art will understand that some of the substituents described above may be considered electron donating or electron withdrawing under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the groups identified above.

The term "halo" includes fluoro, chloro, bromo, iodo and the like.

The term "acyl" includes lower alkanoyls containing 1 to 6 carbon atoms and may be straight or branched. Such groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, trivalent butyryl, pentanoyl, and hexanoyl.

As used herein, heterocyclic groups not only contain at least one sulfur, nitrogen, or oxygen ring atom, but may also contain several such atoms in the ring. Heterocyclic groups contemplated by the present invention may include heteroaromatics and saturated and partially saturated heterocyclic compounds. Such heterocyclic may be monocyclic, bicyclic, tricyclic, or polycyclic and are fused rings. These preferably comprise up to 18 ring atoms and up to 17 ring carbon atoms in total, and up to 25 carbon atoms in total. Heterocyclic is also intended to include so-called benzoheterocyclics. Representative heterocyclics are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, py Ferrazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl , Imidazolinyl, imidazolininyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, N-oxides of nitrogen-containing heterocycles, such as azetidinyl and N-oxides such as pyridyl, pyrazinyl, and pyrimidinyl. Heterocyclic groups may be unsubstituted, or may be monosubstituted or multisubstituted with electron withdrawing groups and / or electron donors.

Preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridylyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl . Preferred heterocyclics are 5- or 6-membered heterocyclic compounds. Particularly preferred heterocyclics are furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. Most preferred heterocyclics are furyl and pyridyl.

Preferred compounds are those in which n is 1, but di (n = 2), tri (n = 3), and tetrapeptide (n = 4) are also expected to be within the scope of the present invention.

Preferred values of R are aryl lower alkyls, in particular benzyl, in particular their phenyl rings being those which are unsubstituted or substituted by groups or / and electron withdrawing groups such as halo (eg F).

Preferred R ₁ is H or lower alkyl. Most preferred R ₁ group is methyl.

Preferred electron giving substituents and / or electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocy Click, guanidine, tetravalent ammonium, lower alkenyl, lower alkynyl, sulfonium salt, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, mercapto, mercury Captoalkyl, alkylthio, and alkyldithio. The term "sulfide" includes mercapto, mercaptoalkyl, and alkylthio, while the term disulfide includes alkyldithio. Particularly preferred electron donating substituents and / or electron withdrawing groups are halo or lower alkoxy, most preferred is fluoro or methoxy. Such preferred substituents are any of the groups of formula (Ib) and / or (IIb), for example R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ' ₆ , R as defined herein. Or any one of ₇ , R ₈ or / and R ₅₀ .

The ZY groups representing R ₂ and R _{3 include} hydroxy, alkoxy such as methoxy and ethoxy, and aryloxy such as phenoxy; Thioalkoxy such as thiomethoxy, thioethoxy; Thioaryloxy such as thiophenoxy; Amino; Alkylamino such as methylamino, ethylamino; Arylamino, such as anilino; Lower dialkylamino such as dimethylamino; Trialkyl ammonium salts, hydrazino; Alkylhydrazinos and arylhydrazinos, such as N-methylhydrazino, N-phenylhydrazino, carboalkoxy hydrazino, aralkyloxycarbonyl hydrazino, aryloxycarbonyl hydrazino; N-hydroxylamino (-NH-OH), lower alkoxy amino [(NHOR ₁₈ ), where R ₁₈ is lower alkyl], N-lower alkylhydroxy amino [(NR ₁₈ ) OH, where R ₁₈ is lower alkyl , N-lower alkyl-O-lower alkylhydroxyamino, [eg, N (R ₁₈ ) OR ₁₉ , wherein R ₁₈ and R ₁₉ are independently lower alkyl], and O-hydroxylamino ( -O-NH ₂ ); Alkylamido such as acetamido; Trifluoroacetamido; Lower alkoxyamino, (eg, NH (OCH ₃ )); And heterocyclic amino such as pyrazoylamino.

Preferred heterocyclic groups representing R ₂ and R ₃ are moieties corresponding to a monocyclic 5- or 6-membered heterocyclic moiety or a partially or fully saturated form thereof:

Wherein n is 0 or 1;

R ₅₀ is H or an electron withdrawing group or electron giving group;

A, E, L, J, and G are independently CH or heteroatoms selected from the group consisting of N, O, S;

When n is 0, G is CH, or when at least two of A, E, L, J, and G are heteroatoms, they are heteroatoms selected from the group consisting of NH, O, and S.

When n is 0, the heteroaromatic moiety is a 5-membered ring, but when n is 1, the heterocyclic moiety is a 6-membered monocyclic heterocyclic moiety. Preferred heterocyclic moieties are such heterocyclic heterocyclics.

If the ring described above comprises a nitrogen ring atom, the N-oxide form is also expected to be within the scope of the present invention.

When R ₂ or R ₃ is heterocyclic of the above formula, it may be bonded to the main chain by ring carbon atoms. When n is 0, R ₂ or R ₃ may be further bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R ₂ and R ₃ are hydrogen, aryl (eg phenyl), aryl alkyl (eg benzyl), and alkyl.

It is to be understood that preferred R ₂ and R ₃ groups may be unsubstituted, or the electron donor may be monosubstituted or multisubstituted with a group and / or electron withdrawing group. R ₂ and R ₃ are independently unsubstituted or lower alkoxy (eg methoxy, ethoxy, etc.), N-hydroxyamino, N-lower alkylhydroxyamino, N-lower alkyl-O-lower Electron withdrawing groups such as alkyl, and alkylhydroxyamino and / or electron donor are preferably hydrogen, lower alkyl substituted with groups.

R ₂ and R ₃ One of them is preferably hydrogen.

It is preferable that n is 1.

, 또는

인 것이 특히 바람직하다.n is 1 and R ₂ and R ₃ One of them is more preferably hydrogen. In this example, R ₂ is hydrogen and R ₃ is lower alkyl or ZY; Z is O, NR ₄ , or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

, or

Is particularly preferred.

In another particularly preferred embodiment, n is 1, R ₂ is hydrogen and R ₃ is unsubstituted or an electron donating group or / and an electron withdrawing group, NR ₄ OR ₅ , Or lower alkyl which may be substituted with ONR ₄ R ₇ . In another particularly preferred embodiment n is 1, R ₂ is hydrogen and R ₃ is unsubstituted or hydroxy or lower alkoxy, NR ₄ OR ₅ Or lower alkyl substituted with ONR ₄ R ₇ . Wherein R ₄ , R ₅ , and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, the aryl group may be unsubstituted or substituted with an electron withdrawing group, and R ₁ is lower alkyl. In this embodiment, aryl is phenyl, which is most preferably unsubstituted or substituted with halo.

R ₂ is hydrogen, and R ₃ is hydrogen, an unsubstituted or at least one electron giving alkyl group substituted with a group and / or an electron withdrawing group, or ZY. In this preferred embodiment, R ₃ is more preferably hydrogen, an alkyl group such as methyl unsubstituted or substituted by an electron donating group, or NR ₄ OR ₅ or ONR ₄ R ₇ . Wherein R ₄ , R ₅ , and R ₇ are independently hydrogen or lower alkyl. The electron donating group is lower alkoxy, particularly preferably methoxy or ethoxy.

R ₂ and R ₃ Is independently hydrogen, lower alkyl, or ZY;

Z is O, NR ₄ , or PR ₄ ;

Y is hydrogen or lower alkyl

, 또는

인 것이 바람직하다.ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

, or

Is preferably.

It is also preferred that R is aryl lower alkyl. Most preferred aryl for R is phenyl. Most preferred R group is benzyl. In a preferred embodiment, the aryl group can be unsubstituted or substituted with an electron donor group and / or an electron withdrawing group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halo, especially fluoro.

Preferred R ₁ is lower alkyl, in particular methyl.

More preferably R is aryl lower alkyl and R ₁ is lower alkyl.

More preferred compounds are those of formula Ib, wherein n is 1; R ₂ is hydrogen; R ₃ is hydrogen, an lower alkyl group substituted with an electron donating group or an electron withdrawing group, in particular methyl, or ZY; R is aryl lower alkyl such as aryl, benzyl and R ₁ is lower alkyl. Here, the aryl group is unsubstituted or the electron donor is substituted with a group or an electron withdrawing group. In this example, R ₃ is a lower alkyl group, in particular methyl, NR ₄ OR ₅ or ONR ₄ R ₇ , which can be substituted by a group of electrons such as hydrogen, lower alkoxy (eg methoxy, ethoxy etc.) More preferred. Here, these groups have been defined above.

The most preferred compound used is a compound of formula IIb.

Formula IIb]

Where

Ar is aryl, in particular phenyl, unsubstituted or substituted with at least one electron donating group or electron withdrawing group, especially halo;

R ₁ is lower alkyl, in particular lower alkyl comprising 1-3 carbon atoms;

R ₃ is as defined herein, but in particular hydrogen, unsubstituted, or lower alkyl substituted with a group or an electron withdrawing group, or ZY. In this embodiment, R ₃ is more preferably hydrogen, an alkyl group unsubstituted or substituted by an electron-giving group, or NR ₄ OR ₅ or ONR ₄ R ₇ . R ₃ is —CH ₂ —Q, wherein Q is in particular lower alkoxy comprising 1-3 carbon atoms; Most preferably it is NR ₄ OR ₅ or ONR ₄ R ₇ . Wherein R ₄ is hydrogen or alkyl containing 1-3 carbon atoms, R ₅ is hydrogen or alkyl containing 1-3 carbon atoms, and R ₇ is hydrogen or alkyl containing 1-3 carbon atoms to be.

Most preferred R ₁ is CH ₃ . Most preferred R ₃ is CH ₂ -Q, wherein Q is methoxy.

Most preferred aryl is phenyl. Most preferred halo is fluoro.

Most preferred compounds include the following:

(R) -2-acetamido-N-benzyl-3-methoxy-propionamide;

O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;

O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;

N-acetyl-D-phenylglycine benzylamide;

D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide;

D-1,2- (O-methylhydroxyamino) -2-acetamido acetate benzylamide.

It should be understood that various combinations and modifications of the Markush groups of R ₁ , R ₂ , R ₃ , R, and n disclosed herein are contemplated within the scope of the present invention. Moreover, the present invention also encompasses compounds and compositions comprising one or more components of each group of R ₁ , R ₂ , R ₃ , n, and R and various combinations thereof. Thus, for example, the present invention provides that R ₁ may be one or more of the substituents listed above, which combine with any and all of the substituents of R ₂ , R ₃ , and R for each value of n. Expect that.

The compounds used in the present invention may comprise one or more asymmetric carbons and may exist in racemic and optically active forms.

The arrangement around each asymmetric carbon may be in D or L form. It is well known in the art that the arrangement around a chiral carbon atom can also be described as R or S in the Cahn-Prelog-Ingold nomenclature system. All variations of arrangement around each asymmetric carbon, including racemic mixtures, and pure enantiomers, diastereomers, or mixtures of both, as well as various pure enantiomers and diastereomers are contemplated by the present invention.

In the backbone, there is an asymmetry in the carbon atom to which the R ₂ and R ₃ groups are attached. When n is 1, the compounds of the present invention belong to formula III:

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ' ₆ , R ₇ , R ₈ , R ₅₀ , Z, and Y are as previously defined.

As used herein, the term "configuration" will refer to the arrangement around the carbon atom to which the R ₂ and R ₃ groups are attached, although other chiral centers may be present in the molecule. Thus, when referring to a specific arrangement such as D or L, it should be understood to mean the D or L stereoisomer at the carbon atom to which R ₂ and R ₃ are attached. However, it also includes all possible enantiomers and diastereomers at other chiral centers that are possibly present in the compound.

The compounds of the invention relate to all optical isomers, for example, the compounds of the invention are L-stereoisomers or D-stereoisomers (at the carbon atoms to which R ₂ and R ₃ are attached). Such stereoisomers can be found in mixtures of L and D, for example racemic mixtrures. D stereoisomers are preferred.

More preferred are compounds of formula III having an R configuration, preferably substantially pure enantiomers, wherein substituent R is benzyl unsubstituted or substituted with at least one halo group, and R ₃ is CH ₂ -Q Q is lower alkoxy containing 1-3 carbon atoms and R ₁ is methyl. Preferably, R is benzyl substituted with at least one halo group which is an unsubstituted benzyl or fluoro group.

Depending on the substituents, the present compounds may also form addition salts. All such forms are contemplated within the scope of this invention including mixtures of stereoisomeric forms.

The preparation of the compounds used is disclosed in US Pat. Nos. 5,378,729 and 5,773,475, both of which are incorporated herein by reference.

The compounds used in the present invention can be used as described in formulas Ib and / or IIb, or in the form of salts because of their basic properties by the presence of free amino groups. Thus, compounds of formula (lb) and / or (lb) form salts with a wide range of inorganic and organic acids, including pharmaceutically acceptable acids. Salts with pharmaceutically acceptable acids are of course useful in the preparation of formulations in which improved water solubility is most advantageous.

Such pharmaceutically acceptable salts also have therapeutic efficacy. Such salts are salts of organic acids such as tartaric acid, acetic acid, citric acid, maleic acid, benzoic acid, perchloric acid, glycolic acid, glucoic acid, succinic acid, aryl sulfonic acid, (e.g., p-toluene sulfonic acid, benzene sulfonic acid), phosphoric acid, malonic acid, and the like. As well as salts of inorganic acids such as hydrochloric acid, iodic acid, bromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid.

The present invention also relates to a method for the prevention, alleviation, and / or treatment of a disease or condition as described above in a mammal, including a human, comprising administering at least one compound of formula (Ib) and / or (IIb). will be.

The compounds used in the present invention are preferably used in therapeutically effective amounts.

The physician will determine the dosage of the present therapeutic agent that will be most appropriate and will vary depending on the form of administration and the particular compound selected, and moreover it will vary depending on the patient being treated, the age of the patient and the type of disease being treated. The physician will generally wish to start the treatment at a dose that is substantially less than the optimal dose of the compound and increase the dose by a small increase until the optimum effect is reached under the circumstances. When the composition is administered orally, higher amounts of active will be required to produce the same effect as the lower amount given parenterally. The compounds are useful in the same way as comparable therapeutic agents and the dosage level is generally of the same order of magnitude as those used for these other therapeutic agents.

In a preferred embodiment, the compound of the present invention is administered in an amount ranging from about 1 mg to about 100 mg per kilogram of body weight per day. This dosage regime can be adjusted by the physician to provide the optimum therapeutic response. Patients in need thereof may be treated with a dosage of a compound of the invention of at least 100 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day, and most preferably at least 400 mg / day. . At a maximum, patients in need thereof may be treated at a dose of up to 6 g / day, preferably up to 3 g / day, more preferably up to 1 g / day, and most preferably up to 400 mg / day.

In another preferred embodiment, the daily dose is increased until a certain daily dose is reached, so that it is maintained for further treatment.

In another preferred embodiment, several separate doses may be administered daily. For example, it may be administered three times a day, preferably twice a day. More preferably, once daily administration.

In another preferred embodiment, the compounds of the invention are administered in an amount such that the plasma concentration, calculated as the mean for a plurality of treated patients, is between 7 and 8 μg / ml (lowest) and 9 and 12 μg / ml (highest) Can be.

A patient in need thereof may be treated with a compound of the present invention for at least 1 week, preferably at least 2 weeks, more preferably at least 4 weeks, most preferably at least 8 weeks. The dosage can be reduced proportionally as indicated by the urgency of the therapeutic situation.

Compounds of Formula (Ib) and / or (IIb) may be administered in a convenient manner such as by oral, intravenous (where water-soluble), intramuscular, intrathecal, or subcutaneous routes. Oral and / or intravenous (i.v.) administration is preferred.

The pharmaceutical compositions of the invention are prepared for the therapeutic regime as described above, in particular for the treatment at the dosages as described above, and as described above in the administration cycle or as specified in the preferred embodiment of the invention. And plasma concentrations as described above for the route of administration.

In another preferred embodiment, the methods of the present invention as described above for the treatment of a mammal, including a human in need thereof, can be used to prevent, alleviate, or / or prevent headaches such as CSD-related disorders, and / or migraines. And administering a compound of the present invention in combination with administering an additional active agent for treatment. Compounds of the invention and additional active agents for the prevention, alleviation, or / and treatment of CSD-related disorders and / or headaches may be administered together, for example in a single dosage form, or, for example, in separate dosage forms. It may be administered separately. Accordingly, the pharmaceutical compositions of the present invention may comprise a compound of the present invention as defined above and may further comprise additional active agents for the prevention, alleviation, and / or treatment of CSD-related disorders and / or headaches. The pharmaceutical composition may comprise a single dosage form or may comprise a separate dosage form comprising a first composition comprising a compound of the invention as defined above and a second composition for additional active agents. .

The compounds of the present invention can be used for the preparation of pharmaceutical compositions as described above.

Compounds of formula (Ib) and / or (IIb) are, for example, orally administered with an inert diluent or absorbable edible carrier, wrapped in a solid or soft shell gelatin capsule, compressed into tablets, or a fool of everyday food. Can be included directly in For oral therapeutic administration, the active compounds of formula (Ib) and / or (IIb) are included with excipients to include ingestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. It can be used in the form of. The composition and preparation should comprise at least 1% of the active compound of formula (Ib) and / or (IIb). The proportion of the composition and the preparation may, of course, vary and may conveniently be between about 5% and about 80% of the weight of the unit. In such therapeutically useful compositions the amount of active compound of formula (Ib) and / or (IIb) is such that a suitable dosage is obtained. Preferred compositions or preparations according to the invention comprise between about 10 mg and about 6 g of active compound of formula (Ib) and / or (IIb).

Tablets, troches, pills, capsules, and the like may also include: binders such as tragacanth gum, acacia, corn starch, or gelatin; Excipients such as dicalcium phosphate; Disintegrating agents such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And flavoring agents, such as sucrose, lactose, or saccharin, are added, or fragrances such as peppermint, evergreen oil, or cherry spice. When the dosage unit form is a capsule, it may comprise, in addition to the substance of the above form, a liquid carrier.

Various other materials may be present as coatings or to alter the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs include active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, dyes, and fragrances such as cherry or orange flavors. Of course, any substance used to prepare any dosage unit form must be pharmaceutically pure and substantially non toxic in the amount used. Moreover, the active compounds may be included in sustained release preparations and formulations. For example, sustained release dosage forms are contemplated, where the active ingredient is limited to ion exchange resins, which may optionally be coated with a diffusion barrier coating to alter the release characteristics of the resin.

The active compound can also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures and oils thereof. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (which are water soluble at this time) or dispersions and sterile powders for the instant preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringabilty is present. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium comprising water, ethanol, polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycols, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coatings such as recithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surface active agents. Prevention of microbial action can be caused by various antibacterial and antimicrobial agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Delayed absorption of the injectable compositions can be brought about by use in agents that delay absorption, such as aluminum monostearic acid and gelatin compositions.

Sterile injectable solutions, together with the various other ingredients enumerated above, are prepared by adding the required amount of active compound to a suitable solvent and then, if necessary, by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and lyophilization, which adds any additional desired ingredients from those solutions previously sterilized-filtered.

As used herein, a “pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media, coatings, antibacterial and antibacterial agents, isotonic agents and to pharmaceutically active substances well known in the art. Delayed absorption formulations. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is envisaged. Supplementary active ingredients can also be included in the compositions.

It is particularly advantageous to produce parenteral compositions in which dosage unit form is convenient for administration and uniform in dosage. Dosage unit form as used herein refers to physically discrete units adapted as unitary dosages for the mammalian patient being treated; Each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specificity of the novel dosage unit forms of the present invention is defined as: (a) the unique properties of the active substance from which a particular therapeutic effect is obtained, and (b) the diseased state, which is deteriorated physically as described in detail herein. It is determined or directly depends on the innate limitations in the synthetic technique, such as active substances for the treatment of diseases in existing patients.

The main active ingredient is synthesized for convenient and effective administration in an effective amount with a suitable pharmaceutically acceptable carrier in dosage unit form as previously described. The unit dosage form may comprise, for example, the main active compound in an amount ranging from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in about 1 to about 750 mg / ml of the carrier. In the case of compositions comprising supplementary active ingredients, the dosage is determined by the relationship with the routine dosage and method of administration of said ingredient.

As used herein, the terms "patient" or "subject" include warm-blooded animals, preferably cats, dogs, horses, cattle, pigs, mice, and humans, for example. Refers to mammals such as primates. Preferred patients are humans.

The term “treat” refers to alleviating pain associated with a disease or condition, or alleviating a disease or condition in a patient.

The compounds of the present invention are administered in an amount effective for analgesia in a patient suffering from the pain forms described above. This amount corresponds to the therapeutically effective amount described above.

The examples below show the properties of SPM 927 to reduce pain in clinical trials of animals with CSD.

The material used was SPM 927, a synonym for Harkoseride. The standard chemical name is (R) -2-acetamide-N-benzyl-3-methoxypropionamide.

FIG. 1 depicts experimental settings modified from rat brain atlas of Paxinos and Watson.

This study aimed to demonstrate that pre-treatment with SPM 927 (3 doses) affects electrophysiological and biochemical symptoms in a rat model of migraine (cortical proliferation inhibition, CSD). This showed that SPM 927 treatment reduced the levels of CSD-induced direct current (DC) potential and calcitonin genetic-related peptide (CGRP) levels in the blood.

Materials and methods

All animal experiments were conducted in accordance with the National Institutes of Health (NIH) guidelines on the care and use of laboratory animals and were approved by the Ethics Committee of the National Center for Laboratory Animals (Kuopio, Finland). All 77 adult male Wistar rats, purchased from Harlan, The Netherlands, weighing 250-350 g, were used in this experiment. Animals were raised in a light-controlled environment (lit from 7 am to 9 pm) at standard temperature (22 ± 1 ° C.). Animals were divided into the following groups:

15 rats treated with SPM 927 (3 mg / kg; i.p.) for 30 minutes prior to the above CSD symptoms

15 rats treated with SPM 927 (10 mg / kg; i.p.) for 30 minutes prior to onset of CSD symptoms

15 rats treated with SPM 927 (30 mg / kg; i.p.) for 30 minutes prior to onset of CSD symptoms

15 rats treated with valproic acid (250 mg / kg; i.p.) for 30 minutes prior to onset of CSD symptoms

15 rats treated with Vehicle (2 ml / kg; i.p.) for 30 minutes prior to onset of CSD symptoms

2 sham rats without the above CSD symptoms (topical NaCl use) and no other treatment

Subgroups:

10 rats for DC-Pensitive, CBF, and blood pH, pO ₂ , pCO ₂ , glucose and mean arterial blood pressure (rats die 30 minutes after CSD, brain fresh-frozen).

5 rats for jugular vein cannulation (CGRP sampling) and cortical and dura mater CGRP immunocytotochemistry (rats die 5 minutes after CSD)

Mice were anesthetized with Equithesin (3 ml / kg) and placed in a stereotactic frame. The rectal temperature was maintained at 37.0 ± 1.0 ° C. with a homeothermic blanket system. A polyethylene catheter was inserted into the femoral artery to monitor arterial blood pressure and blood samples for pH, pO ₂ , pCO ₂ and glucose of the artery were taken. The arterial blood gas was measured with the i-STAT handheld clinical analyzer (I-STAT), the arterial blood pressure was monitored with a Cardiocap II blood pressure analyzer (datex-Ohmeda, Helsinki, Finland), and blood glucose was measured using a standard glucose meter (Arkray, Japan). The measurements were made 10 minutes before the CSD symptoms and 5 minutes after the CSD symptoms. The skin was opened by a medical incision and contracted laterally. Three cranial burr holes were drilled in one row. First on the frontal cortex, second on the frontoparietally, third on the parietally (FIG. 1). Intact rigid laser-Doppler flow probes (Oxyflow, Oxford Optronics, UK) and non-invasive tungsten electrodes for direct current (DC) potential shift measurements for monitoring CBF It was placed in the burr holes of the forehead and forehead on the membrane. The laser-Doppler flow probes were placed in areas free of large soft membrane and hard membrane vessels to minimize large-vessel contribution to the signal. In the DC-potential measurement, the reference electrode was fixed to the neck. CSD was induced to one side by placing a sheet of KCl-immersed (3.0 M) filter paper on the parietal opening for 5 minutes. The KCl exposure was completed by flushing the opening with saline and placing a sheet of dry filter paper on the opening. The CBF and DC-potential were monitored starting 5 minutes before CSD and continuing to 30 minutes after KCl exposure.

At 15 minutes (n = 15) after 60 minutes of CSD symptom onset, mice were deeply anesthetized with pentobarbital, first with PBS and then transcardially with 4% paraformaldehyde heart in PBS. Perfusion. After perfusion, the supratentorial dura (as a whole) and coronal brain blocks were excised and postfixed by soaking the coronary brain blocks in the same fixative for 4 hours. Brain dura mater was used for whole-mount preparation and treated by CGRP immunostaining. In the cerebral dura mater specimen, a 12 μm thick cryosection or 40 μm thick floating section on a glass slide from a block frozen in isopentane frozen in 20% sucrose and cooled with liquid nitrogen for 48 hours. floating sections) were cut with cryostat. In summary, after PBS washing and blocking serum incubation, the sections were reacted with primary antibody for 48 hours at 4 ° C. (rabbit anti-CGRP, Sigma RBI). The rinsed sections were incubated with a biotinylated secondary antibody for 2 hours (goat anti-rabbit, Vector Labs, CA) and then incubated with an avidin-biotin complex for 2 hours ( ABC Elite Kit, Vector Labs), the peroxidase comprising the avidin-biotin complex was made visible with 0.05% Ni-diaminobenzidine (Ni-DAB) and 0.02% H ₂ O ₂ . Finally, the sections were rinsed, air-dried, coverglassed and examined with a Leica 3000RB microscope. The density of the immune response was measured from 3 to 4 sections (3 to 4 different microscopic regions from the dura mater) in each animal.

After anesthesia (before CSS), the catheter was placed into the right jugular vein. 0.250 ml of blood was drawn through a baseline catheter. Additional samples were taken 10-15 minutes and 20-25 minutes after CSD initiation during time course experiments. Samples were prepared in prepared Eppendorf tubes containing protease inhibitor aprotinin (1000 KU, Bayer, Germany) and Pefabloc ™ (1 mg / ml, Boehringer Mannheim, Germany). Stored immediately, refrigerated centrifuged and stored at -80 ° C. The samples were acidified with trifluoroacetic acid and centrifuged at 6000 g for 20 minutes. The supernatant was extracted with Sep-Pak C-18 cartridge (Millipore, Waters, UK). Eluate was concentrated (dry) and dissolved in EIA buffer. CGRP concentrate was detected using a commercial CGRP EIA kit (S-3006, Bachem Distribution GmbH) according to the manufacturer's instructions.

All values were calculated as mean ± standard deviation (SD) and the differences were considered statistically significant at the P <0.05 level. Statistical analysis was performed using StatsDirect statistical software. Differences between means were analyzed using one-way analysis of variance (ANOVA). Dunnet's post-hoc test was applied in multiple comparisons with the control.

result

SPM 927 has shown that it has the following effects:

-Inhibits cortical diffusion inhibition (Table 1)

Reduced CSD-induced release of CGRP in the blood over time (Table 2)

SPM 927 inhibits cortical diffusivity inhibition, ie reduces the value of direct current (DC) potential. group DC figures Saline (n = 10) 4.5 ± 0.6 SPM 927 (3 mg / kg) (n = 10) 4.2 ± 0.4 SPM 927 (10 mg / kg) (n = 10) 3.3 ± 0.4 SPM 927 (30 mg / kg) (n = 10) 3.5 ± 0.6 Valproic acid (250 mg / kg) (n = 10) 3.7 ± 0.3

SPM 927 decreases cortical diffuse inhibition (CSD) induced CGRP release expressed as a percentage of baseline levels during the first 25 minutes after CSD induction. group base line 10 to 15 minutes 20 to 25 minutes Saline (n = 10) 100 ± 0% 150 ± 30% 190 ± 24% SPM 927 (3 mg / kg) (n = 5) 100 ± 0% 126 ± 45% 35 ± 7% SPM 927 (10 mg / kg) (n = 5) 100 ± 0% 114 ± 27% 66 ± 31% SPM 927 (30 mg / kg) (n = 5) 100 ± 0% 92 ± 53% 71 ± 12% Valproic acid (250 mg / kg) (n = 5) 100 ± 0% 56 ± 8% 71 ± 15%

conclusion

The results indicate that SPM 927 is useful for the treatment of acute migraine headaches, prophylactic treatment of migraine headaches and other forms of chronic headaches and / or CSD-related disorders.

Claims (38)

The following preparations for the preparation of pharmaceutical compositions useful for the prevention, alleviation, and / or treatment of pain conditions associated with and / or caused by headaches and / or cortical diffuse inhibition (CSD). Use of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof: Formula Ib

Wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl R is unsubstituted or at least one electron withdrawing group and / or at least one electron atom is substituted with a group; R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, respectively Is unsubstituted or substituted with at least one electron donor group and / or at least one electron withdrawing group; R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or ZY, wherein R ₂ and R ₃ are unsubstituted or at least one electron withdrawing group and / or at least one electron atom is substituted with a group; R ₂ and R ₃ Heterocyclic in the furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, py Ferrazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl , Imidazolinyl, imidazolininyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, Azetidinyl, or when N is present in heterocyclic, is an N-oxide thereof; Z is O, S, S (O) _a , NR ₄ , NR ' ₆ , PR ₄ , or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, Y is unsubstituted, or at least one The electron donor may be substituted with a group or / and at least one electron withdrawing group, wherein the heterocyclic has the same meaning as in R ₂ and R ₃ , and when Y is halo, Z is a chemical bond, or ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , or N ⁺ R ₅ R ₆ R ₇ ,

Is; R ' ₆ is hydrogen or unsubstituted or lower alkyl, lower alkenyl, or lower alkynyl, which may be substituted by a group with at least one electron withdrawing group and / or at least one electron; R ₄ , R ₅ , and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ , and R ₆ are independently unsubstituted, Or at least one electron withdrawing group and / or at least one electron note can be substituted with a group; R ₇ is R ₆ or COOR ₈ or COR ₈ and R ₇ may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donor; R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group is unsubstituted or at least one electron withdrawing group and / or at least one electron donor may be substituted with a group; n is 1-4; a is 1-3 Use according to claim 1, characterized in that the headache is a chronic headache. Use according to claim 1 or 2, characterized in that the headache is a migraine. 4. Use according to claim 3 for the manufacture of a medicament for the treatment of acute migraine headaches. The use according to any one of claims 1 to 4, wherein one of R ₂ and R ₃ is hydrogen. The use according to any one of claims 1 to 5, wherein n is one. 7. Use according to any of the preceding claims, characterized in that at least one of R ₂ and R ₃ is hydrogen and n is 1. 8. Use according to any one of claims 1 to 7, wherein R is aryl lower alkyl and R ₁ is lower alkyl. The compound of claim 1, wherein R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR ₄ , or PR ₄ ; Y is hydrogen or lower alkyl, or ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

, or

Use, characterized in that. The compound of claim 9, wherein R ₂ is hydrogen and R ₃ is lower alkyl or ZY; Z is O, NR ₄ , or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

, or

Use, characterized in that. 10. The compound of claim 9, wherein R ₂ is hydrogen and R ₃ is unsubstituted or lower alkyl, NR ₄ OR ₅ , or / and ONR ₄ R ₇ substituted with a group or / and at least one electron withdrawing group. Use, characterized in that. The compound of claim 9, wherein R ₃ is unsubstituted or substituted with hydroxy, lower alkyl or lower alkoxy, NR ₄ OR ₅ , or / and ONR ₄ R ₇ ego, R ₄ , R ₅ , and R ₇ are independently hydrogen or lower alkyl, R is an aryl lower alkyl group which may be unsubstituted or substituted with at least one electron withdrawing group, And R ₁ is lower alkyl. 13. Use according to claim 12, wherein the aryl is phenyl, unsubstituted or substituted with halo. The compound according to any one of claims 1 to 13, wherein the compound is (R) -2-acetamido-N-benzyl-3-methoxy-propionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide; D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide; or D-1,2- (O-methylhydroxyamino) -2-acetamido acetic acid benzylamide. Use according to any one of claims 1 to 14, characterized in that the compound has the formula (IIb) or a pharmaceutically acceptable salt thereof. Formula IIb]

Where Ar is phenyl unsubstituted or substituted with at least one halo group; R ₃ is CH ₂ -Q and Q is lower alkoxy containing 1-3 carbon atoms; R ₁ is lower alkyl containing 1-3 carbon atoms. Use according to claim 15, wherein Ar is unsubstituted phenyl. Use according to claim 15 or 16, characterized in that the halo is fluoro. The method according to any one of claims 15 to 17, R ₃ is CH ₂ -Q, Wherein Q is alkoxy containing 1-3 carbon atoms, Ar is an unsubstituted phenyl. Use according to any one of the preceding claims, characterized in that the compound is in the R configuration with the following formula or a pharmaceutically acceptable salt thereof.

R Where R is benzyl unsubstituted or substituted with at least one halo group; R ₃ is CH ₂ -Q, wherein Q is lower alkoxy containing 1-3 carbon atoms; R ₁ is methyl. 20. Use according to claim 19, characterized in that it is substantially pure enantiopure. 21. Use according to claim 19 or 20, wherein R is unsubstituted benzyl. 22. Use according to any of claims 19 to 21, wherein halo is fluoro. The method according to any one of claims 19 to 22, R ₃ is CH ₂ -Q, And wherein Q is alkoxy containing 1-3 carbon atoms and R is unsubstituted benzyl. The method according to any one of claims 1 to 4, And said compound of formula (Ib) is (R) -2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof. The use according to claim 24, wherein said compound is a substantially pure mirror image. The method according to any one of claims 1 to 25, Wherein said pharmaceutical composition is prepared for treatment with a dosage of a compound of at least 100 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day, most preferably at least 400 mg / day Use. The method according to any one of claims 1 to 26, The pharmaceutical composition is prepared for treatment at a dose of up to 6 g / day, preferably up to 3 g / day, more preferably up to 1 g / day, most preferably up to 400 mg / day Usage. The method according to any one of claims 1 to 27, And wherein said pharmaceutical composition is prepared for treatment at a daily dose that is increased until a predetermined daily dose is reached and maintained for further treatment. The method according to any one of claims 1 to 28, Use of the pharmaceutical composition, characterized in that it is prepared for treatment in three doses per day, preferably twice daily, more preferably once daily. The method according to any one of claims 1 to 29, The pharmaceutical composition is prepared for administration which results in a plasma concentration of 7 to 8 μg / ml (lowest) and 9 to 12 μg / ml (highest) calculated as an average for a number of treatment subjects . The method according to any one of claims 1 to 30, And wherein said pharmaceutical composition is prepared for treatment for at least 1 week, preferably at least 2 weeks, more preferably at least 4 weeks, most preferably at least 8 weeks. 32. The use according to any one of claims 1 to 31, wherein said pharmaceutical composition is prepared for oral administration. The method according to any one of claims 1 to 32, And wherein said pharmaceutical composition comprises additional active agents for the prevention, alleviation, and / or treatment of headaches and / or CSD-related disorders. The method of claim 33, wherein The pharmaceutical composition comprises a single dose form; Or an individual comprising a first composition comprising a compound as defined in any one of claims 1 and 5 to 25 and a second composition for the prevention, alleviation, and / or treatment of headaches and / or CSD-related disorders. Use comprising a dose dose form. The method according to any one of claims 1 to 34, And wherein said pharmaceutical composition is prepared for mammalian administration. 36. The method of claim 35 wherein And wherein said pharmaceutical composition is prepared for human administration. (a) a compound as defined in any one of claims 1 and 5 to 25, and (b) A pharmaceutical composition comprising additional active agents for the prevention, alleviation, and / or treatment of headaches and / or CSD-related disorders. The method of claim 37, A single composition or for the prevention, alleviation, and / or treatment of a first composition comprising a compound as defined in any one of claims 1 and 5 to 25 and a headache or / and a CSD-related disorder. A pharmaceutical composition comprising an individual dosage form comprising a second composition.

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